Factor H interferes with the adhesion of sickle red cells to vascular endothelium : a novel disease-modulating molecule

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Lombardi , E , Matte , A , Risitano , A M , Ricklin , D , Lambris , J D , De Zanet , D , Jokiranta , S T , Martinelli , N , Scambi , C , Salvagno , G , Bisoffi , Z , Colato , C , Siciliano , A , Bortolami , O , Mazzuccato , M , Zorzi , F , De Marco , L & De Franceschi , L 2019 , ' Factor H interferes with the adhesion of sickle red cells to vascular endothelium : a novel disease-modulating molecule ' , Haematologica , vol. 104 , no. 5 , pp. 919-928 . https://doi.org/10.3324/haematol.2018.198622

Title: Factor H interferes with the adhesion of sickle red cells to vascular endothelium : a novel disease-modulating molecule
Author: Lombardi, Elisabetta; Matte, Alessandro; Risitano, Antonio M.; Ricklin, Daniel; Lambris, John D.; De Zanet, Denise; Jokiranta, Sakari T.; Martinelli, Nicola; Scambi, Cinzia; Salvagno, Gianluca; Bisoffi, Zeno; Colato, Chiara; Siciliano, Angela; Bortolami, Oscar; Mazzuccato, Mario; Zorzi, Francesco; De Marco, Luigi; De Franceschi, Lucia
Contributor: University of Helsinki, Medicum
Date: 2019-04-30
Language: eng
Number of pages: 10
Belongs to series: Haematologica
ISSN: 0390-6078
URI: http://hdl.handle.net/10138/303683
Abstract: Sickle cell disease is an autosomal recessive genetic red cell disorder with a worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of clinical complications of sickle cell disease. In this study we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from patients with sickle cell disease. There was also deposition of C3b on sickle red cell membranes, which is promoted locally by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar "stop-and-go" motion of sickle cell red blood cells on tumor factor-alpha-activated vascular endothelial surfaces. Using the C3b/iC3b binding plasma protein factor H as an inhibitor of C3b cell-cell interactions, we found that factor H and its domains 19-20 prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells. We documented that factor H acts by preventing the adhesion of sickle red cells to P-selectin and/or the Mac-1 receptor (CD11b/CD18), supporting the activation of the alternative pathway of complement as an additional mechanism in the pathogenesis of acute sickle cell related vaso-occlusive crises. Our data provide a rationale for further investigation of the potential contribution of factor H and other modulators of the alternative complement pathway with potential implications for the treatment of sickle cell disease.
Subject: ALTERNATIVE COMPLEMENT PATHWAY
P-SELECTIN
BLOOD-CELLS
MOUSE MODEL
3 BINDING
IN-VIVO
ACTIVATION
ERYTHROCYTES
PHOSPHATIDYLSERINE
CRIZANLIZUMAB
3111 Biomedicine
3122 Cancers
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